Cellular abnormalities of blood vessels as targets in cancer
Introduction
Despite convincing evidence that tumor growth is angiogenesis-dependent and that attacking the blood supply might induce tumor regression, knowledge of the abnormalities of tumor blood vessels that make this approach feasible is surprisingly limited. Tumor blood vessels, like normal ones, are composed of endothelial cells, mural cells (pericytes or smooth muscle cells) and basement membrane. All of these are abnormal in tumor blood vessels. Here, we review the current understanding of these abnormalities and their potential as therapeutic targets.
Just as the vasculature of each normal organ reflects the distinctive local conditions, blood vessels of tumors mirror their environment. The bizarre nature of tumors results in bizarre blood vessels. Tumor vessels are exceptionally variable in size, shape and branching pattern, and are not organized in the conventional hierarchy of arterioles, capillaries and venules (Figure 1a,b). However, the severity and types of vascular defects vary with the particular conditions within a tumor [1].
Most tumor models in animals use fast-growing tumor xenografts, often in ectopic locations [2]. By comparison, human cancer tends to be slower growing, and the location is determined by the natural history of the disease. Vascularity of tumors varies, tending to be greatest in regions of active growth, often at the periphery, and absent in regions of necrosis. Such regional differences in vascular density can complicate the interpretation of estimates of tumor vascularity, but tumors with a high microvascular density tend to be more aggressive and prone to metastases [3].
Section snippets
Endothelial cells
Tumors acquire their vasculature as they grow by secreting factors that stimulate the formation of new vessels. The dominant process of vessel growth is angiogenesis by sprouting of existing vessels 4., 5. (Figure 2a). Here, the balance between endothelial cell division and apoptosis shifts towards proliferation [5]. Growth of tumor vessels has many features in common with sprouting angiogenesis in wound healing and other conditions but, although the general regulatory mechanisms are likely to
Pericytes
Pericytes are key cells in vascular development, stabilization, maturation and remodeling 23., 24.. From both structural and functional studies, pericytes are known to be intimately associated with endothelial cells. Indeed, an important criterion in the identification of pericytes is their position, along with endothelial cells, within the vascular basement membrane. Pericytes are present on capillaries, postcapillary venules and collecting venules throughout the body. Nonetheless, pericytes
Vascular basement membrane
Vascular basement membrane is a self-assembled, supramolecular complex of proteins, glycoproteins and proteoglycans that tightly envelops endothelial cells and pericytes of blood vessels. Type IV collagen, laminin, fibronectin and heparan sulfate proteoglycan are among the main components [33••]. In tumors, defects in epithelial basement membrane are well documented features of invasion [34], but the vascular basement membrane has received less attention. Once thought to be incomplete or
Response of tumor vessels to angiogenesis inhibitors
From their name, angiogenesis inhibitors would be expected to block the growth of new vessels and perhaps stop tumor growth but not necessarily affect existing vessels or cause tumor shrinkage. However, inhibitors of VEGF signaling not only stop angiogenesis but also cause regression of some tumor vessels and may reduce tumor size 42., 43., 44.••, 45.•.
Inhibition of VEGF signaling causes robust and rapid changes in all components of the wall of tumor vessels (Figure 1c) [46•]. Within 24 hours,
Conclusions
Tumor blood vessels have multiple abnormalities resulting from the bizarre environment in which they grow. Conventional vascular hierarchy, where arterioles connect to capillaries that connect to venules, is absent in tumors. Endothelial cells of tumor vessels do not form a tight barrier, and pericytes are loosely attached. The aberrant distribution of vascular basement membrane — created when vessels grow and left behind when they regress — provides a historical record of the dynamic nature of
Update
Most tumors have few or no functional lymphatic vessels, yet metastases to lymph nodes are common in some types of cancer. He et al. [54] report that growth of lymphatic vessels around tumors requires intact VEGFR-3 signaling but not the involvement of bone marrow progenitor cells. Few lymphatics are present around tumors in mice with heterozygous loss-of-function mutation of VEGF-C, and none are present when VEGFR-3 signaling is blocked. Isaka et al. [55] show that, even when present,
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Supported in part by the US National Institutes of Health grants HL24136 and HL59157 from the National, Heart, Lung and Blood Institute and P50 CA90270 and CA82923 from the National Cancer Institute, and funding from AngelWorks Foundation and the Vascular Mapping Project (DMM).
Glossary
- Angiogenesis inhibitors
- Strictly speaking, these are agents that block the growth of new blood vessels. However, these agents can also cause regression of existing tumor vessels and normalize ones that do not regress.
- Pericytes
- Also known as mural cells or periendothelial cells, these cells are located in the wall of capillaries, venules and most tumor vessels. Pericytes and endothelial cells produce the vascular basement membrane that envelops them.
- Vascular normalization
- The tendency toward
References (56)
- et al.
Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells
Blood
(2004) - et al.
Dissecting tumour pathophysiology using intravital microscopy
Nat Rev Cancer
(2002) - et al.
Tumor-associated endothelial cells with cytogenic abnormalities
Cancer Res
(2004) - et al.
In vivo angiogenic phenotype of endothelial cells and pericytes induced by vascular endothelial growth factor-A
J Histochem Cytochem
(2004) Basement membranes: structure, assembly and role in tumour angiogenesis
Nat Rev Cancer
(2003)- et al.
Regulation of angiogenesis in vivo by ligation of integrin α5β1 with the central cell-binding domain of fibronectin
Am J Pathol
(2000) - et al.
Regression of established tumors and metastases by potent vascular endothelial growth factor blockade
Proc Natl Acad Sci USA
(2003) - et al.
Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors
J Clin Invest
(2003) - et al.
Age-related changes in vascular endothelial growth factor dependency and angiopoietin-1-induced plasticity of adult blood vessels
Circ Res
(2004) - et al.
Tumor oxygenation in hormone-dependent tumors during vascular endothelial growth factor receptor-2 blockade, hormone ablation, and chemotherapy
Cancer Res
(2000)